The invention relates to substituted amino-furan-2-yl-acetic acid derivatives and substituted amino-thien-2-yl-acetic acid derivatives, to processes for their preparation, to medicaments containing them, to the use of those compounds in the preparation of medicaments for the treatment of, inter alia, pain and migraine, and to pharmaceutical compositions containing them.
The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for highly effective therapies for the targeted treatment of chronic and non-chronic pain in a manner that is fair to the patient, which is understood to mean the successful and satisfactory treatment of pain for the patient.
Conventional opioids such as morphine are highly effective in the therapy of severe to the most severe pain. However, their use is limited by the known side-effects, such as respiratory depression, vomiting, sedation, constipation and tolerance. In addition, they are less effective in neuropathic or incidental pain, from which tumor patients in particular suffer.
Opioids develop their analgesic action by binding to receptors in the cell membrane which belong to the family of the so-called G-protein-coupled receptors. In addition, there are further receptors and also ion channels which are substantially involved in the system of pain formation and pain transmission, for example the N-methyl-D-aspartate ion channel (NMDA ion channel), via which a substantial part of the communication of synapses proceeds and through which the calcium ion exchange between a neuronal cell and its surroundings is controlled (see, for example, P. D. Leeson, L. L. Iversen, J. Med. Chem. 37 (1994) 4053-4067).
Important findings regarding the physiological importance of ion-channel-selective substances have been made possible by the development of the xe2x80x9cpatch-clampxe2x80x9d technique, by means of which the action of NMDA antagonists (i.e. antagonists of the NMDA ion channel) on the metabolism of calcium inside the cell can be demonstrated.
The object underlying the present invention is to provide novel compounds suitable for the therapy of pain. In addition, it is desirable that these substances have only minimal, if any, of the side-effects that usually occur with the use of opioids such as morphine, such as nausea, vomiting, dependence, respiratory depression or constipation.
That object is achieved by compounds having the general structure (I) and by their pharmaceutically acceptable salts: 
wherein
A represents oxygen or sulfur,
R1 represents aryl, (C1-6-alkyl)-aryl, heterocyclyl or (C1-6-alkyl)-heterocyclyl,
R2 represents H, C1-12-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, aryl, (C1-6-alkyl)-aryl, heterocyclyl or (C1-6-alkyl)-heterocyclyl,
R3, R4 and R5 each independently of the others represents H, OH, SH, F, Cl, Br, I, xe2x80x94CN, NO2, C1-2-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, aryl, (C1-6-alkyl)-aryl, heterocyclyl, (C1-6-alkyl)-heterocyclyl, xe2x80x94SiR6R7R8, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)mxe2x80x94R9 wherein n=1, 2, 3 or 4 and m=0, 1, 2, 3 or 4, xe2x80x94(CH2)oxe2x80x94Spxe2x80x94(CH2)qxe2x80x94R10 wherein o=1, 2, 3 or 4, p=1 or 2 and q=0, 1, 2, 3 or 4, xe2x80x94(CH2)rxe2x80x94CO2R11 wherein r=0, 1, 2, 3 or 4, xe2x80x94(CH2)sxe2x80x94OCOR12 wherein s=0, 1, 2, 3 or 4, or xe2x80x94COR13,
R6, R7 and R8 each independently of the others represents C1-6-alkyl or phenyl,
R9 and R10 each independently of the other represents H, CH3, aryl, heterocyclyl or xe2x80x94C(xe2x95x90O)xe2x80x94C1-6-alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-6-alkyl)-aryl or xe2x80x94C(xe2x95x90O)-aryl,
R11 represents H, C1-6-alkyl or CH2-phenyl,
R12 represents C1-6-alkyl or aryl,
R13 represents H, C1-6-alkyl, aryl, heterocyclyl or NR14R15,
R14 and R15 each independently of the other represents H, C1-6-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, aryl, (C1-6-alkyl)-aryl, heterocyclyl or (C1-6-alkyl)-heterocyclyl, or R14 and R15 together form xe2x80x94(CH2)kxe2x80x94 wherein k=4, 5 or 6,
wherein
alkyl represents a non-cyclic hydrocarbon radical which is straight-chain or branched and is saturated or unsaturated and is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents,
cycloalkyl represents an alicyclic hydrocarbon radical which is saturated or unsaturated and is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents,
aryl is a radical selected from the group of 
heterocyclyl represents a monocyclic or polycyclic organic radical in which at least one ring contains one hetero atom or 2, 3, 4 or 5 identical or different hetero atoms selected from the group of N, O and S, the radical being saturated or unsaturated and being unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 each independently of the others represents H, OR28, S(O)tR29 wherein t=0, 1 or 2, SO2OR30, F, Cl, Br, I, xe2x80x94CN, NO2, C1-12-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, phenyl or (C1-6-alkyl)-phenyl, wherein phenyl is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents, heterocyclyl, (C1-6-alkyl)-heterocyclyl, xe2x80x94CO2R31 or xe2x80x94NR32R33,
R28, R29, R30 and R31 each independently of the others represents H, C1-12-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, phenyl or (C1-6-alkyl)-phenyl, wherein phenyl is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents, heterocyclyl, (C1-6-alkyl)-heterocyclyl or xe2x80x94NR34R35,
and
R32 and R33 each independently of the other represents H, C1-6-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, phenyl, (C1-6-alkyl)-phenyl, heterocyclyl or (C1-6-alkyl)-heterocyclyl, or R32 and R33 together form xe2x80x94(CH2)hxe2x80x94 wherein h=4, 5 or 6,
and
R34 and R35 each independently of the other represents H, C1-6-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, phenyl, (C1-6-alkyl)-phenyl, heterocyclyl or (C1-6-alkyl)-heterocyclyl, or R34 and R35 together form xe2x80x94(CH2)gxe2x80x94 wherein g=4, 5 or 6.
Accordingly, the compounds according to the invention having the general structure (I) are either amino-furan-2-yl-acetic acid derivatives having the general structure (I-A) or amino-thien-2-yl-acetic acid derivatives having the general structure (I-B): 
It has been found that the compounds having the general structure (I-A) or (I-B) bind selectively to the glycine binding site of the NMDA ion channel and accordingly are suitable for the treatment of pain. The same is also true of (4-methoxy-phenylamino)-thien-2-yl-acetic acid, which is known as such from the prior art (N. A. Petasis et al., Tetrahedron (1997), 16463-16470) but for which no medicinal indication is disclosed in the prior art. The present invention therefore relates also to that compound, in so far as its use in a medicament, for the preparation of a medicament, especially for the treatment of pain, and a pharmaceutical composition containing it are concerned.
Within the scope of this invention, the term xe2x80x9carylxe2x80x9d means phenyls and naphthyls. Each aryl radical may be unsubstituted or mono- or poly-substituted, it being possible for the aryl substituents to be identical or different and to be at any desired and possible position of the aryl. Aryl is advantageously an unsubstituted or substituted phenyl. Particularly preferred aryl radicals for the purposes of the invention are mono- or di-substituted phenyl.
Within the scope of this invention, the terms xe2x80x9cC1-12-alkylxe2x80x9d and xe2x80x9cC1-6-alkylxe2x80x9d include acyclic saturated or unsaturated hydrocarbon radicals which may be branched- or straight-chain and may be unsubstituted or mono- or poly-substituted, having from 1 to 12 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) and from 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) carbon atoms, respectively, that is to say C1-12-alkanyls and C1-6-alkanyls, C2-12-alkenyls and C2-6-alkenyls and C2-12-alkynyls and C2-6-alkynyls. xe2x80x9cAlkenylsxe2x80x9d have at least one Cxe2x80x94C double bond and xe2x80x9calkynylsxe2x80x9d have at least one Cxe2x80x94C triple bond. Alkyl is advantageously selected from the group of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-octyl, n-nonyl, n-decyl, n-dodecyl; ethenyl (vinyl), ethynyl, propenyl (xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94C(xe2x95x90CH2)xe2x80x94CH3), propynyl (xe2x80x94CH2xe2x80x94Cxe2x80x94CH, xe2x80x94Cxe2x89xa1Cxe2x80x94CH3), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, octenyl and octynyl.
For the purposes of this invention, the term xe2x80x9cC3-8-cycloalkylxe2x80x9d means cyclic hydrocarbon radicals having 3, 4, 5, 6, 7 or 8 carbon atoms, it being possible for the radicals to be saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted by identical or different substituents. C3-8-Cycloalkyl is advantageously selected from the group of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
The term xe2x80x9cheterocyclylxe2x80x9d denotes a 3-, 4-, 5-, 6- or 7-membered cyclic organic radical which contains at least one hetero atom, optionally 2, 3, 4 or 5 hetero atoms, wherein the hetero atoms are identical or different and are selected from the group containing oxygen, nitrogen and sulfur, and the cyclic radical is saturated or unsaturated and may be unsubstituted or mono- or poly-substituted. The heterocycle may also be part of a bicyclic or polycyclic system; for example, a benzene ring may be fused to the heterocycle. Examples of preferred heterocyclyl radicals are furanyl, thienyl (thiophene), indolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and their benzo-fused derivatives. The bond to the compound having the general structure (I) (or (II), (III) and (IV)) can be made via any desired and chemically possible ring member of the heterocyclyl radical.
For the purposes of the present invention, the expressions xe2x80x9c(C1-6-alkyl)-C3-8-cycloalkyl,xe2x80x9d xe2x80x9c(C1-6-alkyl)-heterocyclylxe2x80x9d and xe2x80x9c(C1-6-alkyl)-arylxe2x80x9d mean that the cycloalkyl, heterocyclyl or aryl radical is bonded to the compound having the general structure (I) (or (II), (III) or (IV)) via a C1-6-alkyl group.
In connection with xe2x80x9calkyl,xe2x80x9d xe2x80x9calkanyl,xe2x80x9d xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynyl,xe2x80x9d the term xe2x80x9csubstitutedxe2x80x9d within the scope of this invention is understood to mean the substitution of a hydrogen atom by, for example, F, Cl, Br, I, xe2x80x94CN, NH2, NH-alkyl, NH-aryl, NH-alkyl-aryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(heterocyclyl)2, N(alkyl-OH)2, NO, NO2, SH, S-alkyl, S-aryl, S-alkyl-aryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-alkyl-aryl, O-heterocyclyl, O-alkyl-OH, CHO, C(xe2x95x90O)C1-6-alkyl, C(xe2x95x90S)C1-6-alkyl, C(xe2x95x90O)aryl, C(xe2x95x90S)aryl, C(xe2x95x90O)C1-6-alkyl-aryl, 
wherein n=1, 2 or 3, C(xe2x95x90S)C1-6-alkyl-aryl, C(xe2x95x90O)-heterocyclyl, C(xe2x95x90S)-heterocyclyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(xe2x95x90O)NH2, C(xe2x95x90O)NH-alkyl, C(xe2x95x90O)NHaryl, C(xe2x95x90O)NH-heterocyclyl, C(xe2x95x90O)N(alkyl)2, C(xe2x95x90O)N(alkyl-aryl)2, C(xe2x95x90O)N(heterocyclyl)2, SO-alkyl, SO2-alkyl, SO2-alkyl-aryl, SO2NH2, SO3H, SO3-alkyl, cycloalkyl, aryl or by heterocyclyl; polysubstituted radicals being understood to be radicals that are polysubstituted, for example di- or tri-substituted, either at different atoms or at the same atom, for example trisubstituted at the same carbon atom, as in the case of CF3 or xe2x80x94CH2CF3, or at different positions, as in the case of xe2x80x94CH(OH)xe2x80x94CHxe2x95x90CClxe2x80x94CH2Cl. Polysubstitution can be carried out with the same or with different substituents. For the purposes of the present invention, xe2x80x9calkylxe2x80x9d in this connection particularly preferably means methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, tert-butyl, CH2xe2x80x94OH or CF3.
With regard to xe2x80x9caryl,xe2x80x9d xe2x80x9cphenyl,xe2x80x9d xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9ccycloalkyl,xe2x80x9d xe2x80x9cmonosubstitutedxe2x80x9d or xe2x80x9cpolysubstitutedxe2x80x9d is understood to mean within the scope of this invention the mono- or poly-substitution, for example di-, tri- or tetra-substitution, of one or more hydrogen atoms of the ring system by a suitable substituent. If the meaning of such suitable substituents in connection with xe2x80x9caryl,xe2x80x9d xe2x80x9cphenyl,xe2x80x9d xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d is not defined elsewhere in the description or in the claims, suitable substituents are F, Cl, Br, I, CN, NH2, NH-alkyl, NH-aryl, NH-alkyl-aryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(heterocyclyl)2, N(alkyl-OH)2, NO, NO2, SH, S-alkyl, S-cycloalkyl, S-aryl, S-alkyl-aryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-aryl, O-alkyl-aryl, O-heterocyclyl, O-alkyl-OH, CHO, C(xe2x95x90O)C1-6-alkyl, C(xe2x95x90S)C1-6-alkyl, C(xe2x95x90O)aryl, C(xe2x95x90S)aryl, C(xe2x95x90O)C1-6-alkyl-aryl, 
wherein n=1, 2 or 3, C(xe2x95x90S)C1-6-alkyl-aryl, C(xe2x95x90O)-heterocyclyl, C(xe2x95x90S)-heterocyclyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(xe2x95x90O)NH2, C(xe2x95x90O)NH-alkyl, C(xe2x95x90O)NHaryl, C(xe2x95x90O)NH-heterocyclyl, C(xe2x95x90O)N(alkyl)2, C(xe2x95x90O)N(alkyl-aryl)2, C(xe2x95x90O)N(heterocyclyl)2, S(O)-alkyl, S(O)-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO3H, CF3, xe2x95x90O, xe2x95x90S; alkyl, cycloalkyl, aryl and/or heterocyclyl; at one atom or optionally at different atoms (it being possible for a substituent itself to be substituted). Polysubstitution is carried out with the same or with different substituents. When xe2x80x9carylxe2x80x9d represents phenyl, the phenyl ring is optionally substituted by one or more substituents R16, R17, R18, R19 and R20 as defined above for the general structure (I).
Pharmaceutically acceptable salts within the scope of this invention are those salts of the compounds according to the invention having the general structure (I) which are physiologically tolerable when used pharmaceuticallyxe2x80x94especially when used in mammals and/or humans. Such pharmaceutically acceptable salts can be formed, for example, with inorganic or organic acids or, where the compounds according to the invention are acids, especially carboxylic acids, with bases.
The pharmaceutically acceptable salts of the compounds according to the invention having the general structure (I) are preferably formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. If the compounds according to the invention are acids, especially carboxylic acids, the pharmaceutically acceptable salts can also be formed by reaction with bases, such as sodium hydrogen carbonate or sodium carbonate. The salts formed are, inter alia, hydrochlorides, hydrobromides, phosphates, carbonates, hydrogen carbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutamates, or sodium salts. Also preferred are solvates and, especially, the hydrates of the compounds according to the invention, which can be obtained, for example, by crystallization from aqueous solution.
The compounds according to the invention having the general structure (I) always have at least one center of asymmetry, which is denoted by * in the formula below: 
The compounds according to the invention of the general formula (I) can therefore be in the form of their racemates, in the form of the pure enantiomers and/orxe2x80x94provided a further center of asymmetry is presentxe2x80x94in the form of the pure diastereoisomers, or in the form of mixtures of those enantiomers and diastereoisomers, both in the depicted form and in the form of pharmaceutically acceptable salts thereof. The mixtures may be present in any desired mixing ratio of the stereoisomers.
Preference is given to those compounds having the general structure (I) which are characterised in that
R1 represents aryl or heterocyclyl1,
R2 represents H, C1-12-alkyl, (C1-6-alkyl)-C3-8-cycloalkyl, aryl or (C1-6-alkyl)-aryl,
R3, R4 and R5 each independently of the others represents H, OH, SH, Cl, Br, C1-12-alkyl, C3-8-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, aryl, (C1-6-alkyl)-aryl, heterocyclyl1, (C1-6-alkyl)-heterocyclyl1, xe2x80x94SiR6R7R8, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)mxe2x80x94R9 wherein n=1, 2, 3 or 4 and m=0, 1 or 2, xe2x80x94(CH2)oxe2x80x94Spxe2x80x94(CH2)qxe2x80x94R10 wherein o=1, 2, 3 or 4, p=1 or 2 and q=0, 1 or 2, xe2x80x94(CH2)rxe2x80x94CO2R11 wherein r=0, 1, 2 or 3, xe2x80x94(CH2), xe2x80x94OCOR12 wherein s=0, 1 or 2, or xe2x80x94COR13,
R6, R7 and R8 each independently of the others represents C1-6-alkyl or phenyl,
R9 and R10 each independently of the other represents H, CH3, aryl, heterocyclyl or xe2x80x94C(xe2x95x90O)xe2x80x94C1-6-alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-6-alkyl)-aryl or xe2x80x94C(xe2x95x90O)-aryl,
R11 represents H, C1-6-alkyl or CH2-phenyl,
R12 represents C1-6-alkyl or aryl,
R13 represents C1-6-alkyl or aryl, 
xe2x80x83wherein aryl represents
heterocyclyl represents a monocyclic or polycyclic organic radical in which at least one ring contains one hetero atom or 2, 3, 4 or 5 identical or different hetero atoms selected from the group of N, O and S, the radical being saturated or unsaturated and being unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
heterocyclyl1 represents a monocyclic or bicyclic organic radical in which at least one ring is 5- or 6-membered and contains one hetero atom or 2 identical or different hetero atoms selected from the group of N, O and S, the radical being saturated or unsaturated and being unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
R16, R17, R18, R19 and R20 each independently of the others represents H, OR28, S(O)tR29 wherein t=0 or 2, SO2OR30, F, Cl, Br, I, xe2x80x94CN, NO2, C1-12-alkyl, C3 g-cycloalkyl, (C1-6-alkyl)-C3-8-cycloalkyl, phenyl or (C1-6-alkyl)-phenyl, wherein phenyl is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents, heterocyclyl1, (C1-6-alkyl)-heterocyclyl1, xe2x80x94CO2R31 or xe2x80x94NR32R33,
R28, R29, R30 and R31 each independently of the others represents H, C1-6-alkyl or phenyl, and
R32 and R33 each independently of the other represents H, C1-6-alkyl, (C1-6-alkyl)-phenyl, or R32 and R33 together form xe2x80x94(CH2)hxe2x80x94 wherein h=4, 5 or 6.
Of those compounds, particular preference is given to those in which
R1 represents aryl or heterocyclyl2,
R2 represents H, methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, n-hexyl,
R3, R4 and R5 each independently of the others represents H, OH, SH, Br, Cl, C1-6-alkyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, xe2x80x94SiR6R7R8, xe2x80x94CH2OH, xe2x80x94CH2xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94CH3, xe2x80x94(CH2)xe2x80x94Spxe2x80x94(CH2)qxe2x80x94R10 wherein p=1 or 2 and q=0 or 1, xe2x80x94(CH2)rxe2x80x94CO2R11 wherein r=0 or 1, or xe2x80x94COR13,
R6, R7 and R8 each independently of the others represents methyl, tert-butyl or phenyl,
R10 represents H, methyl, ethyl, 2-furyl, 2-thienyl or xe2x80x94C(xe2x95x90O)xe2x80x94CH3,
R11 represents H, methyl, ethyl or tert-butyl,
R13 represents methyl, 
xe2x80x83wherein aryl represents 
xe2x80x83heterocyclyl2 represents
R16, R17, R18, R19 and R20 each independently of the others represents H, OR28, S(O)tR29 wherein t=0, F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, CF3 or xe2x80x94CO2R31,
R28, R29 and R31 each independently of the others represents H, methyl, ethyl, xe2x80x94CF3 or phenyl,
Xxe2x80x94Y represents CR38xe2x80x94CR39, CR38xe2x80x94N or Nxe2x80x94CR39,
R36, R37, R38 and R39 each independently of the others represents H, F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94SH, C1-6-alkyl or xe2x80x94CF3, and
R40 and R41 each independently of the other represents H, F, Cl, Br, I, xe2x80x94CN, xe2x80x94OH, xe2x80x94O-C1-6-alkyl, xe2x80x94SH, xe2x80x94Sxe2x80x94C1-6-alkyl, C1-8-alkyl, CO2xe2x80x94C1-6-alkyl or xe2x80x94Nxe2x95x90N-aryl.
Very particularly preferred compounds having the general structure (I) are those which are characterised in that
R1 represents aryl or heterocyclyl2,
R2 represents H, methyl, ethyl or tert-butyl,
R3 represents H, Cl, methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, xe2x80x94CH2OH, xe2x80x94CH2SH, xe2x80x94CH2xe2x80x94Sxe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2-furan-2-yl, xe2x80x94CH2xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94(Cxe2x95x90O)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94Sxe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94Sxe2x80x94CH2-furan-2-yl, xe2x80x94CH2xe2x80x94CO2methyl or xe2x80x94CH2xe2x80x94CO2ethyl,
R4 represents H, Br, methyl, ethyl, xe2x80x94CH2OH, xe2x80x94CO2methyl, xe2x80x94CO2ethyl or xe2x80x94COmethyl,
R5 represents H, methyl or ethyl, 
xe2x80x83wherein aryl represents R 
xe2x80x83heterocyclyl2 represents
R16 represents H, xe2x80x94O-phenyl, F, Cl, Br, methyl, ethyl, n-propyl, 2-propyl or tert-butyl,
R17 represents H, Cl, methyl, ethyl or CF3,
R18 represents H, F, Cl, Br, I, xe2x80x94CN, xe2x80x94Oxe2x80x94CH3, xe2x80x94Oxe2x80x94CF3, xe2x80x94O-phenyl, methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl or tert-butyl,
R19 represents H, Cl, Br, methyl or ethyl,
R20 represents H or methyl,
Xxe2x80x94Y represents CR38xe2x80x94CR39, CR38xe2x80x94N or Nxe2x80x94CR39,
R36 represents H, methyl or ethyl,
R37 represents H, NO2, Cl, Br, methyl or CF3,
R38 represents H,
R39 represents H, Cl or Br,
R40 represents H, xe2x80x94Nxe2x95x90N-phenyl, xe2x80x94CN, CO2H, CO2-methyl or CO2-ethyl, and
R41 represents H, OH, SH, S-methyl, methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl.
Of those very particularly preferred compounds, special preference is given to those in which
R1 represents 4-trifluoromethoxy-phenyl, 2-phenoxy-phenyl, 4-phenoxy-phenyl, 2-chloro-phenyl, 4-chloro-phenyl, 4-iodo-phenyl, 4-cyano-phenyl, 2-methyl-phenyl, 2-ethyl-phenyl, 4-ethyl-phenyl, 2-(2-propyl)-phenyl, 4-(2-butyl)-phenyl, 4-tert-butyl-phenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 2,4-dibromo-phenyl, 4-chloro-2-fluoro-phenyl, 2-chloro-4-fluoro-phenyl, 4-bromo-2-chloro-phenyl, 2-chloro-4-iodo-phenyl, 3-chloro-2-methyl-phenyl, 4-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 2-chloro-4-methyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 2,4-dibromo-5-methyl-phenyl, 5-nitro-pyridin-2-yl, 3,5-dibromo-pyridin-2-yl, 3,5-dichloro-pyridin-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl, 3,5-dibromo-6-methyl-pyridin-2-yl, pyrazin-2-yl, 5-bromo-pyrimidin-2-yl, 4-carboxyethyl-pyrazol-3-yl, 4-cyano-pyrazol-3-yl, 5-tert-butyl-pyrazol-3-yl, 5-hydroxy-4-(4-phenylazo)-pyrazol-3-yl or 4-cyano-5-thiomethyl-pyrazol-3-yl,
R2 represents H or ethyl,
R3 represents H, Cl, methyl, ethyl, n-propyl, tert-butyl, xe2x80x94CH2OH, xe2x80x94CH2SH, xe2x80x94CH2Sxe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2-furan-2-yl, xe2x80x94CH2xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94(Cxe2x95x90O)xe2x80x94CH3xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94Sxe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94Sxe2x80x94CH2-furan-2-yl or xe2x80x94CH2xe2x80x94CO2ethyl,
R4 represents H, Br, methyl, xe2x80x94CH2OH, xe2x80x94CO2methyl, xe2x80x94CO2ethyl or xe2x80x94C(xe2x95x90O)CH3, and
R5 represents H or methyl.
Particularly preferred compounds according to the invention are those in which R1 represents 3,5-dichlorophenyl and R2 represents H.
Examples of advantageous compounds of the present invention are selected from the following group:
(5-methylsulfanylmethyl-furan-2-yl)-(5-nitro-pyridin-2-ylamino)-acetic acid
(5-bromopyrimidin-2-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
5-[carboxy-(3,5-dichloropyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(3,5-dibromopyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(3,5-dibromo-6-methyl-pyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
(3,5-dibromo-6-methyl-pyridin-2-ylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid
(3,5-dichloro-pyridin-2-ylamino)-(4-methyl-thiophen-2-yl)-acetic acid
(2,4-dibromo-5-methyl-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid
(4-methyl-thiophen-2-yl)-(5-nitro-pyridin-2-ylamino)-acetic acid
(3,5-dichloro-pyridin-2-ylamino)-furan-2-yl-acetic acid
(3,5-dibromopyridin-2-ylamino)-furan-2-yl-acetic acid
(3,5-dibromo-6-methyl-pyridin-2-ylamino)-furan-2-yl-acetic acid
(3-chloro-5-trifluoromethyl-pyridin-2-ylamino)-furan-2-yl-acetic acid
(5-bromopyrimidin-2-ylamino)-furan-2-yl-acetic acid
5-[(3,5-dichloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
(5-hydroxy-4-phenylazo-1H-pyrazol-3-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid ethyl ester
3-{[ethoxycarbonyl-(4-ethoxycarbonyl-5-methyl-furan-2-yl)-methyl]-amino}-1H-pyrazole-4-carboxylic acid ethyl ester
5-[(4-cyano-5-methylsulfanyl-1H-pyrazol-3-ylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(4-cyano-1H-pyrazol-3-ylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(4-bromo-2-chloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
(4-hydroxymethyl-furan-2-yl)-(5-hydroxy-4-phenylazo-1H-pyrazol-3-ylamino)-acetic acid ethyl ester
(4-cyano-5-methylsulfanyl-1H-pyrazol-3-ylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester
(4-bromo-2-chloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester
(3,5-dichloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester
(5-chloro-2-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid ethyl ester
(2,4-dibromo-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid
(5-chloro-2-methyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(2-ethyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(4-sec-butyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(5-methylsulfanylmethyl-furan-2-yl)-(4-trifluoromethoxy-phenylamino)-acetic acid
(2-isopropyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(2,4-dibromo-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(4-tert-butyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(5-chloro-2-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
(2-ethyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
(4-sec-butyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-(2-isopropyl-phenylamino)-acetic acid
(4-tert-butyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
5-[ethoxycarbonyl-(4-iodo-phenylamino)-methyl]-2-methyl-furan-3 carboxylic acid methyl ester
5-[(4-chloro-2-methyl-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
5-[ethoxycarbonyl-(4-phenoxy-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
5-[ethoxycarbonyl-(4-iodo-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(2-chloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(4-chloro-2-methyl-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(2-chloro-4-fluoro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[ethoxycarbonyl-(4-phenoxy-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[(2,3-dichloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
(4-hydroxymethyl-furan-2-yl)-(4-iodo-phenylamino)-acetic acid ethyl ester
(2,4-dichloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester
(4-chloro-2-methyl-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester
(4-hydroxymethyl-furan-2-yl)-(4-phenoxy-phenylamino)-acetic acid ethyl ester
(2,3-dichloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester
(2,3-dichloro-phenylamino)-furan-2-yl-acetic acid ethyl ester
5-[carboxy-(3,5-dibromo-6-methyl-pyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
(5-methylsulfanylmethyl-furan-2-yl)-(pyrazin-2-ylamino)-acetic acid
(3,5-dibromo-pyridin-2-ylamino)-(5-methylsulfanylmethyl-ftiran-2-yl)-acetic acid
(3,5-dibromo-6-methyl-pyridin-2-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
5-[(4-bromo-2-chloro-phenylamino)-carboxy-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
5-[carboxy-(3,5-dichloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester
5-[carboxy-(2-phenoxy-phenylamino)-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester
5-[(4-bromo-2-chloro-phenylamino)-carboxy-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(4-cyano-phenylamino)-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(3,5-dichloro-phenylamino)-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester
5-[(4-bromo-2-chloro-phenylamino)-carboxy-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(3,5-dichloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
(5-tert-butyl-1H-pyrazol-3-ylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid
(4-bromo-2-chloro-phenylamino)-(3-methyl-thiophen-2-yl)-acetic acid
(4-cyano-phenylamino)-(3-methyl-thiophen-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-(3-methyl-thiophen-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-furan-2-yl-acetic acid
[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-(4-phenoxy-phenylamino)-acetic acid ethyl ester
(5-ethoxycarbonylmethyl-thiophen-2-yl)-(5-hydroxy-4-phenylazo-1H-pyrazol-3-ylamino)-acetic acid ethyl ester
{5-1-(4-cyano-1H-pyrazol-3-ylamino)-3-methoxy-2-oxo-propyl]-thiophen-2-yl}-acetic acid ethyl ester
(4-ethyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(3-chloro-2-methyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(4-chloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(5-methylsulfanylmethyl-furan-2-yl)-o-tolylamino-acetic acid
5-[carboxy-(4-chloro-3-trifluoromethyl-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(2-chloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(2-chloro-4-fluoro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(4-chloro-2-fluoro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
5-[carboxy-(2,3-dichloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester
(2,4-dichloro-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid
(4-chloro-3-trifluoromethyl-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid
(2,4-dichloro-phenylamino)-furan-2-yl-acetic acid
(4-chloro-3-trifluoromethyl-phenylamino)-furan-2-yl-acetic acid
(4-iodo-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(2,4-dichloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(4-chloro-3-trifluoromethyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(2-chloro-phenylamino)-(5-methyl sulfanylmethyl-furan-2-yl)-acetic acid
(4-chloro-2-methyl-phenylamino)-(5-methylsulfanyhnethyl-furan-2-yl)-acetic acid
(2-chloro-4-fluoro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(2-chloro-4-methyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
(2,3-dichloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-(4-iodo-phenylamino)-acetic acid
(4-chloro-3-trifluoromethyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
(4-chloro-2-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
(2-chloro-4-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmcthyl)-furan-2-yl]-acetic acid
(4-chloro-3-trifluoromethyl-phenylamino)-(5-ethoxycarbonylmethyl-thiophen-2-yl)-acetic acid
(4-acetyl-3,5-dimethyl-furan-2-yl)-(2-chloro-4-methyl-phenylamino)-acetic acid
(4-acetyl-3,5-dimethyl-furan-2-yl)-(2,3-dichloro-phenylamino)-acetic acid
(3,5-dichloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid
[2,2xe2x80x2]bithiophenyl-5-yl-(3,5-dichloro-phenylamino-acetic acid
(3,5-dichloro-phenylamino)-(5-methyldisulfanylmethyl-furan-2-yl)-acetic acid
(3-chloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid
(3,4-dichloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-(5-methyl-thiophen-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-(5-hydroxymethyl-thiophen-2-yl)-acetic acid
(5-acetylsulfanylmethyl-furan-2-yl)-(3,5-dichloro-phenylamino)-acetic acid
(3,5-dichloro-phenylamino)-(5-ethyl-thiophen-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-(5-n-propyl-thiophen-2-yl)-acetic acid
(3,5-dichloro-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
(3-chloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid
(3,4-dichloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid
(3,5-dichlorophenylamino)-(thiophen-2-yl)-acetic acid ethyl ester
(4-bromofuran-2-yl)-(3,5-dichloro-phenylamino)-acetic acid ethyl ester
(3,5-dichloro-phenylamino)-(5-propylthiophen-2-yl)-acetic acid ethyl ester
(3,5-dichloro-phenylamino)-(3-methylthiophen-2-yl)-acetic acid ethyl ester
(5-tert-butylfuran-2-yl)-(3,5-dichloro-phenylamino)-acetic acid
(3,5-dichlorophenylamino)-[5-(fuiran-2-ylmethyldisulfanylmethyl)-furan-2-yl]-acetic acid
(3,5-dichlorophenylamino)-(5-methyldisulfanylmethylfuran-2-yl)-acetic acid
(3,5-dichlorophenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid
5-acetoxymethylfuran-2-yl-(3,5-dichlorophenylamino)-acetic acid
(3,5-dichlorophenylamino)-thiophen-3-yl-acetic acid
(3,5-dichlorophenylamino)-(5-methylthiophen-2-yl)-acetic acid
(3,5-dichlorophenylamino)-(4-methylthiophen-2-yl)-acetic acid
(5-chlorothiophen-2-yl)-(3,5-dichlorophenylamino)-acetic acid
and their pharmaceutically acceptable salts.
The compounds according to the invention having the general structure (I) 
wherein A, R1, R2, R3, R4 and R5 are as defined above, are obtainable according to a process which is also provided by the present invention. According to the inventive process, an amine having the general structure (II)
R1xe2x80x94NH2xe2x80x83xe2x80x83II 
wherein R1 is as defined above for the general structure (I), is reacted, under the action of an acid, with a glyoxalic acid derivative having the general structure (III) 
wherein R2 is as defined above for the general structure (I), and with a furan having the general structure (IV-A) or a thiophene having the general structure (IV-B) 
wherein R3, R4 and R5 are as defined above for the general structure (I). If the furan derivative (IV-A) is used, the corresponding amino-furan-2-yl-acetic acid derivative having the general structure (I-A) is obtained as the product, whereas the use of the thiophene derivative (IV-B) yields as the product of the 3-component reaction according to the invention the corresponding amino-thien-2-yl-acetic acid derivative having the general structure (I-B).
For the preparation of the furanylacetic acids (IV-A) and thienylacetic acids (IV-B), that is to say the compounds having the general structure (IV) wherein R2 represents H, the glyoxalic acid reaction component (III) is preferably used in the form of its hydrate.
The process according to the invention can be carried out in the presence of small amounts of an inorganic or, especially, organic acid, for example trifluoroacetic acid, preferably in catalytic amounts of approximately from 1 to 10 mol % (based on the starting material (II)). If there is used as the glyoxalic acid derivative having the general structure (III) glyoxalic acid itself (i.e. the compound (III) wherein R2=H) or its hydrate in a slight excess of approximately from 1.01 to 1.5, preferably from 1.05 to 1.25, molar equivalents (based on the compound (II)), the reaction can be carried out without the addition of an acid or of a further reagent by simply mixing the starting compounds (II), (III) and (IV-A) or (IV-B), preferably in an organic solvent, for example acetonitrile, and then stirring at temperatures of from 0xc2x0 C. to 100xc2x0 C.xe2x80x94optionally also as a one-pot process. It is also advantageous to use the furan derivative (IV-A) or thiophene derivative (IV-B) in an excess of, for example, from 1.5 to 4.5 molar equivalents, especially from 2.5 to 3.5 molar equivalents (based on starting material (II)).
In order to achieve maximum conversion of the starting materials to the compounds according to the invention having the general structure (I), a reaction time of from 8 hours to approximately 18 hours, especially 14 hours, is advantageous for the 3-component reaction according to the invention.
Alternatively, it is also possible to carry out the 3-component reaction according to the invention under the action of microwave radiation, whereby the reaction time for largely complete conversion is shortened to a few minutes, for example to from 0.5 minute to 5 minutes. In the case of this procedure, the chosen reaction temperature is preferably from 15xc2x0 C. to 60xc2x0 C., especially approximately 50xc2x0 C. A laboratory microwave from MLS-GmbH (D-88299 Leutkirch, Auenweg 37, Germany), model MLS ETHOS 600 having a power of about 800 W is suitable for the microwave irradiation. The reaction is advantageously carried out, for example, in a pressure-stable Teflon vessel.
The process according to the invention can also be carried out in semi- or fully automated form as the parallel synthesis of a group of compounds according to the invention having the general structure (I). By means of that technique, and by reaction of the compounds (II), (III) and (IV-A) or (IV-B), it is also possible to construct a substance library in the form of an array of compounds. Such a substance library contains the library members, which are the reaction products of the reaction of the compounds (II), (III) and (IV-A) or (IV-B), in the form of individual pure compounds. With the aid of such a substance library, it is possible, for example, to carry out medicinal screening in one or more in vitro screening processes in automated form.
The amines having the general structure (II), the glyoxalic acid derivatives having the general structure (III), the furan derivatives having the general structure (IV-A) and the thiophene derivatives having the general structure (IV-B) used in the process according to the invention are commercially available (from Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Muilheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCI, Japan) or can be prepared by processes generally known in the art.
The compounds according to the invention having the general structure (I) can be isolated both in the depicted form and in the form of a salt. The compound according to the invention having the general structure (I) is usually obtained after the reaction according to the above-described process has taken place and after subsequent conventional working up. The compound having the general structure (I) so obtained or formed in situ without isolation can then be converted into the corresponding salt, for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. If the compounds according to the invention of the general formula (I) are acids, especially carboxylic acids, the salt formation can be effected by addition of a physiologically tolerable base, for example NaHCO3 or sodium carbonate; the formation of the sodium salt in particular is preferred for the carboxylic acids. The salts that are formed are, inter alia, hydrochlorides, hydrobromides, phosphates, carbonates, hydrogen carbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutamates. Formation of the hydrochloride, which is particularly preferred, can also be effected by addition of trimethylsilyl chloride (TMSCl) to the base dissolved in a suitable organic solvent, such as butan-2-one (methyl ethyl ketone), advantageously in the presence of water.
If the compounds having the general structure (I) are obtained in the preparation process according to the invention in the form of racemates or in the form of mixtures of their different enantiomers and/or diastereoisomers, such mixtures can be separated by processes which are well known in the art. Suitable methods are, inter alia, chromatographic separation processes, especially liquid chromatography processes under normal or elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallization processes. By means of such processes it is possible especially to separate from one another, for example by means of HPLC on chiral phase or by means of crystallization, individual enantiomers of diastereoisomeric salts formed with chiral acids, for example (+)-tartaric acid, (xe2x88x92)-tartaric acid or (+)-10-camphorsulfonic acid, orxe2x80x94where acids are concernedxe2x80x94with chiral bases, for example brucine or (xe2x88x92)-ephedrine.
The present invention also provides a medicament containing at least one compound having the general structure (I) as defined above or a pharmaceutical salt thereof, especially the hydrochloride salt. The medicament according to the invention preferably contains at least one of the compounds mentioned by way of example above in substance or in the form of a pharmaceutically acceptable salt, and optionally further active ingredients and excipients.
Such medicaments according to the invention are preferably used in the therapy of pain, for example, acute pain, chronic pain or neuropathic pain. It has also been found that the medicaments according to the invention can also successfully be used in the treatment of migraine, inflammatory and/or allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory diseases, coughs, mental diseases, neurodegenerative diseases, epilepsy, schizophrenia, Alzheimer""s disease, Huntington""s disease, Parkinson""s disease, cerebral ischaemia, cerebral infarct, psychoses caused by increased amino acid levels, strokes, cerebral oedemas, deficiencies of the central nervous system, hypoxia, anoxia, AIDS dementia, encephalomyelitis, Tourette syndrome, perinatal asphyxia, or for anxiolysis.
The present Application relates also to the use of at least one substituted amino-furan-2-yl-acetic acid derivative of formula (I-A) or substituted amino-thien-2-yl-acetic acid derivative of formula (I-B) in the preparation of a medicament for the treatment of pain, migraine, inflammatory and/or allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory diseases, coughs, mental diseases, neurodegenerative diseases, epilepsy, schizophrenia, Alzheimer""s disease, Huntington""s disease, Parkinson""s disease, cerebral ischaemia, cerebral infarct, psychoses caused by increased amino acid levels, strokes, cerebral oedemas, deficiencies of the central nervous system, hypoxia, anoxia, AIDS dementia, encephalomyelitis, Tourette syndrome, perinatal asphyxia, or for anxiolysis.
The present invention also provides pharmaceutical compositions that contain at least one compound having the general structure (I) as defined above, or a pharmaceutically acceptable salt thereof, as well as one or more pharmaceutical excipients.
The medicaments and pharmaceutical compositions according to the invention can be in liquid, semi-solid or solid pharmaceutical dosage forms and can be administered in the form of, for example, injectable solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pellets, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols, and, in addition to at least one compound according to the invention having the general structure (I), they contain, according to the particular formation and depending on the route of administration, pharmaceutical excipients, such as carriers, fillers, solvents, diluents, surface-active substances, colorings, preservatives, disintegrators, glidants, lubricants, flavorings and/or binders. Such excipients may be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, groundnut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and polyoxypropylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potassium carbonate, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talcum, kaolin, pectin, crospovidone, agar and bentonite.
The choice of excipients and the amounts thereof to be used depend on whether the medicament is to be administered by the oral, subcutaneous, parenteral, intravenous, vaginal, pulmonary, intraperitoneal, transdermal, intramuscular, nasal, buccal or rectal route, or locally, for example to infections of the skin, the mucosa and of the eyes. For oral administration there are suitable, inter alia, preparations in the form of tablets, dragxc3xa9es, capsules, granules, drops, juices and syrups, and for parenteral and topical administration and for administration by inhalation there are suitable solutions, suspensions, readily reconstitutable powders for inhalation, and also sprays. Compounds according to the invention having the general structure I in a depot formulation in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, are suitable preparations for percutaneous administration. Forms of preparation for rectal, transmucosal, parenteral, oral or percutaneous administration may release the compounds according to the invention having the general structure (I) in a delayed manner.
The medicaments and pharmaceutical compositions according to the invention are prepared by means, devices, methods and processes which are well known in the art of pharmaceutical formulation, as are described, for example, in xe2x80x9cRemington""s Pharmaceutical Sciences,xe2x80x9d ed. A. R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), especially in Part 8, Chapter 76 to 93.
Accordingly, for a solid formulation, for example, a tablet, the active ingredient of the medicament, i.e. a compound having the general structure (I) or a pharmaceutically acceptable salt thereof, can be granulated with a pharmaceutical carrier, for example conventional tablet constituents such as maize starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example, water, in order to form a solid composition which contains a compound according to the invention or a pharmaceutically acceptable salt thereof in homogeneous distribution. Homogeneous distribution is here understood to mean that the active ingredient is distributed evenly throughout the entire composition, so that the latter can readily be divided into unit dose forms, such as tablets, pills or capsules, which each have the same effectiveness. The solid composition is then divided into unit dose forms. It is also possible for the tablets or pills of the medicament according to the invention or of the compositions according to the invention to be coated or otherwise compounded, in order to prepare a delayed-release dosage form. Suitable coating agents are, inter alia, polymeric acids and mixtures of polymeric acids with materials such as, for example, shellac, cetyl alcohol and/or cellulose acetate.
The amount of active ingredient to be administered to a patient varies and is dependent on the weight, the age and the history of past disease in the patient, and also on the mode of administration, the indication and the severity of the disease. Normally, from 0.1 to 5000 mg/kg, especially from 1 to 500 mg/kg, preferably from 2 to 250 mg/kg body weight of at least one compound according to the invention having the general structure (I) are administered.
The present invention is explained further hereinbelow by means of Examples, without limiting it thereto.